Various medical articles have been designed particularly for contact with a patient's bodily fluids. This contact can be sufficiently long such that calcification of the medical article becomes a concern. Relevant medical articles include, for example, catheters and prostheses. Catheters include percutaneous devices that penetrate the skin to provide access to a bodily system.
Prostheses, i.e., prosthetic devices, are used to repair or replace damaged or diseased organs, tissues and other structures in humans and animals. Prostheses must be generally biocompatible since they are typically implanted for extended periods of time. Specifically, prostheses include artificial hearts, artificial heart valves, annuloplasty rings, ligament repair material, vessel repair structures, surgical patches constructed of mammalian tissue and the like. Prostheses can be constructed from natural materials, synthetic materials or a combination thereof.
Calcification, i.e., the deposit of calcium salts especially calcium phosphate (hydroxyapatite), can occur in and on some materials of a medical article while contacting the patient's bodily fluids. Calcification can affect the performance and structural integrity of medical articles constructed from these calcification sensitive materials, especially over extended periods of time. For example, calcification is the primary cause of clinical failure of bioprosthetic heart valves made from porcine aortic valves or bovine pericardium. Calcification is particularly severe at stress points where suture passes through tissue. Calcification also significantly affects the performance of prostheses constructed from synthetic materials, such as polyurethane.
The importance of bioprosthetic animal heart valves as replacements for damaged human heart valves has resulted in a considerable amount of interest in the effects of calcification on these xenotransplants. Bioprosthetic heart valves from natural materials were introduced in the early 1960's. Bioprosthetic heart valves typically are derived from pig aortic valves or are manufactured from other biological materials such as bovine pericardium. Xenograft heart valves are typically fixed with glutaraldehyde prior to implantation to reduce the possibility of immunological rejection. Glutaraldehyde reacts to form covalent bonds with free amino groups in proteins, thereby chemically crosslinking nearby proteins.
Generally, bioprosthetic heart valves begin failing after about seven years following implantation, and few bioprosthetic valves remain functional after 20 years. Replacement of a degenerating valve prosthesis subjects the patient to additional surgical risk, especially in the elderly and in situations of emergency replacement. While failure of bioprostheses is a problem for patients of all ages, it is particularly pronounced in younger patients. Over fifty percent of bioprosthetic valve replacements in patients under the age of 15 fail in less than five years because of calcification.
Similarly, calcification of polyurethane bladders in artificial hearts and of leaflets in polyurethane valves is potentially clinically significant. Other prostheses made from natural and/or synthetic materials also display clinically significant calcification.
As a result, there is considerable interest in preventing the deposit of calcium on implanted biomaterials, especially heart valves. Research on the prevention of calcification has focused to a considerable extent on the pretreatment of the biomaterial prior to implantation. Detergents (e.g., sodium dodecyl sulfate), toluidine blue or diphosphonates have been used to pretreat tissues in an attempt to decrease calcification by reducing calcium nucleation. Within a relatively short time, these materials tend to wash out of the bioprosthetic material into the bodily fluids surrounding the implant, limiting their effectiveness.
Other approaches to reducing calcification have employed a chemical process in which at least some of the reactive glutaraldehyde moieties are inactivated. Still other approaches have included development of alternative fixation techniques, since evidence suggests that the fixation process itself contributes to calcification and the corresponding mechanical deterioration. In addition, since nonviable cells present in transplanted tissue are sites for calcium deposition, various processes have been developed to remove cellular material from the collagen--elastin matrix of the tissue prior to implantation.
A significant advance toward reducing calcification of bioprostheses was the determination that Al.sup.+3 cations and other multivalent cations inhibit calcification. Biocompatible materials were treated with an acidic, aqueous solution of AlCl.sub.3 prior to implantation. While some of the Al.sup.+3 cations wash away after being removed from the treatment solution, a significant quantity of cations remain joined with the treated materials for extended periods, presumably due to some type of association of the cations with the bioprosthetic material.
The associated Al.sup.+3 cations are found to contribute to significant inhibition of calcium deposition. Furthermore, this effect persists over a significant period, at least several months in a juvenile animal. Treatment with Fe.sup.+3 salts is observed to produce similar reductions in calcification.
Physiologically normal calcification of skeletal and dental tissues and pathological calcification, such as calcification of bioprostheses, have important similarities including the initial deposit of apatitic mineral. These mineral deposits contain calcium and phosphates, and mineral growth takes place at nuclei provided by initial deposits. Nucleation in bone development takes place at structures that have a high concentration of calcium binding phospholipids and high activity of phosphatases, especially alkaline phosphatase. Alkaline phosphatase activity is particularly high in children, which may contribute to the severe calcification problem for bioprostheses implanted into young patients.
Phosphatase activity is found to be inhibited by incubation with AlCl.sub.3 and FeCl.sub.3. This observation suggests that the effect of Al.sup.+3 and Fe.sup.+3 cations in reducing calcification may be due to the inhibition of the phosphatase activity. Alternatively or in addition, the ions may act by substitution into the hydroxyapatite crystal lattice which could prevent growth by destabilizing the crystal.